Phenylethynyl and styryl derivatives of imidazole and fused ring heterocycles

ABSTRACT

This invention relates to a compound and the use of the compound of the formula  
                 
 
     wherein R 1 , R 2 , R 3 , R 4  and R 5  are as defined in the description, A signifies —CH═CH— or —C═C—; and B signifies  
                 
 
     wherein R 6  to R 26 , X and Y are as defined In the specification or a pharmaceutically acceptable salt thereof, for use in pharmaceutical compositions for the treatment or prevention of mGluR5 receptor mediated disorders.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application is a divisional of Ser. No. 09/996,641, filedNov. 28, 2001.

BACKGROUND OF THE INVENTION

[0002] In the central nervous system (CNS) the transmission of stimulitakes place by the interaction of a neurotransmitter, which is sent outby a neuron, with a neuroreceptor.

[0003] Glutamate is the major excitatory neurotransmitter in the brainand plays a unique role in a variety of central nervous system (CNS)functions. The glutamate-dependent stimulus receptors are divided intotwo main groups. The first main group, namely the ionotropic receptors,forms ligand-controlled ion channels. The metabotropic glutamatereceptors (mGluR) belong to the second main group and, furthermore,belong to the family of G-protein coupled receptors.

[0004] At present, eight different members of these mGluR are known andof these some even have sub-types. According to their sequence homology,signal transduction mechanisms and agonist selectivity, these eightreceptors can be sub-divided into three sub-groups:

[0005] mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong togroup II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

[0006] Ligands of metabotropic glutamate receptors belonging to thefirst group can be used for the treatment or prevention of acute and/orchronic neurological disorders such as psychosis, epilepsy,schizophrenia, Alzheimer's disease, cognitive disorders and memorydeficits, as well as chronic and acute pain.

[0007] Other treatable indications in this connection are restrictedbrain function caused by bypass operations or transplants, poor bloodsupply to the brain, spinal cord injuries, head injuries, hypoxia causedby pregnancy, cardiac arrest and hypoglycaemia. Further treatableindications are Huntington's chorea, amyotrophic lateral sclerosis(ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathicparkinsonism or parkinsonism caused by medicaments as well as conditionswhich lead to glutamate-deficiency functions, such as e.g. musclespasms, convulsions, migraine, urinary incontinence, nicotine addiction,opiate addiction, anxiety, vomiting, dyskinesia and depressions.,

[0008] Disorders mediated full or in part by mGluR5 are for exampleacute, traumatic and chronic degenerative processes of the nervoussystem, such as Alzheimer's disease, senile dementia, Parkinson'sdisease, Huntington's chorea,,amyotrophic lateral sclerosis and multiplesclerosis, psychiatric diseases such as schizophrenia and anxiety,depression and pain. Selective mGluR5 antagonists are especially usefulfor the treatment of anxiety and pain.

SUMMARY OF THE INVENTION

[0009] The present invention is a method of treatment of mGluR5 receptormediated disorders by administering a therapeutically effective amountphenylethenyl and phenylethynyl derivatives of the compound formula

[0010] wherein

[0011] R¹, R², R³, R⁴ and R⁵, are independently selected from the groupconsisting of hydrogen, lower alkyl, —(CH₂)_(n)-halogen, lower alkoxy,—(CH₂)_(n)—NRR′, —(CH₂)_(n)—N(R)—C(O)-lower alkyl, aryl or heteroarylwhich is unsubstituted or substituted by one or more lower alkylresidues;

[0012] R, R′ and R″ are independently selected from the group consistingof hydrogen and lower alkyl;

[0013] A is selected from the group consisting of —CH=CH—, or —C≡C—; and

[0014] B is selected from the group consisting of

[0015] wherein

[0016] R⁶ is selected from the group consisting of hydrogen, lower alkyl—(CH₂)_(n)—C(O)OR and halogen;

[0017] R⁷ is selected from the group consisting of hydrogen, loweralkyl, —(CH₂)_(n)—C(O)OR′, halogen, nitro, unsubstituted heteroaryl andheteroaryl substituted by lower alkyl or cycloalkyl;

[0018] R⁸ is selected from the group consisting of hydrogen, loweralkyl, —(CH₂)_(n)—OH, —(CH₂)_(n)—C(O)OR″ and aryl;

[0019] R⁹ is lower alkyl;

[0020] R¹⁰ is selected from the group consisting of hydrogen, loweralkyl and halogen;

[0021] R¹¹ is selected from the group consisting of hydrogen and alkyl;

[0022] R¹² is —(CH₂)_(n)—N(R)—C(O)-lower alkyl;

[0023] R¹³ selected from the group consisting of hydrogen and loweralkyl;

[0024] R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are independently selected from the groupconsisting of, hydrogen, lower alkyl, —(CH₂)_(n)-halogen and loweralkoxy;

[0025] R¹⁸, R¹⁹ and R²⁰ are independently selected from the groupconsisting of hydrogen, lower alkyl, —(CH₂)_(n)-halogen and loweralkoxy;

[0026] R²¹ is hydrogen or lower alkyl;

[0027] R²² is selected from the group consisting of hydrogen, loweralkyl and lower alkyl with at least one substituent selected from thegroup consisting of hydroxy or halogen;

[0028] R²³ is selected from the group consisting of hydrogen, loweralkyl, lower alkanoyl and nitro;

[0029] R²⁴, R²⁵ and R²⁶, are independently selected from the groupconsisting of hydrogen and lower alkyl;

[0030] n is 0, 1, 2, 3, 4, 5 or 6;

[0031] X is —CH₂—, —O—or —S—; and

[0032] Y is —CH═ or —N═;

[0033] or a pharmaceutically acceptable salt thereof.

[0034] Some compounds of the present formula I are known compounds andare described in the literature. For example the synthesis of1-methyl-2-phenylethynyl-1H-imidazole,1-methyl-5-phenylethynyl-1H-imidazole and1-methyl-4-phenylethynyl-1H-imidazole as well as the synthesis of thecorresponding phenylethenyl derivatives is described in Chem. Pharm.Bull. 1987, 35(2), 823-828. The compounds have been prepared bypalladium catalyzed reaction of corresponding halogen-1,3-azoles withphenylacetylene or styrene.1-Methyl-2-(4-methoxy-phenylethynyl)-1H-imidazole can be synthesized asnonlinear optical chromophore according to Chem Mater. 1994, 6(7),1023-1032. The preparation of2-alkyl-5-phenylethynyl-1H-imidazole-4-carboxaldehydes as intermediatesfor the manufacture of substituted imidazoles for use as angiotensin IIblockers has been described in WO 91/00277.1-Methyl-5-(2-phenyl-ethenyl)-1H-imidazole has also been prepared asintermediate for the synthesis of heterocyclic food mutagens accordingto Environ. Health Perspect. 1986, 67, 41-45.

[0035] It has now surprisingly been found that compounds of formula Iare metabotropic glutamate receptor antagonists having valuabletherapeutic properties.

[0036] The present invention also relates to novel compounds of theformula

[0037] wherein

[0038] R¹, R², R³, R⁴ and R⁵ are independently selected from the groupconsisting of, hydrogen, lower alkyl, —(CH₂)_(n)-halogen, lower alkoxy,—(CH₂)_(n)—NRR′, —(CH₂)_(n)—N(R)—C(O)-lower alkyl, aryl, unsubstitutedheteroaryl and heteroaryl substituted by one or more lower alkylresidues;

[0039] R, R′ and R″ are selected from the group consisting hydrogen andlower alkyl;

[0040] B is selected from the group consisting of

[0041] wherein

[0042] R⁶ is selected from the group consisting of hydrogen, loweralkyl, —(CH₂)_(n)—C(O)OR and halogen;

[0043] R⁷ is selected from the group consisting of hydrogen, loweralkyl, —(CH₂)_(n)—C(O)OR′, halogen, nitro, unsubstituted heteroaryl andheteroaryl substituted by lower alkyl or cycloalkyl;

[0044] R⁸ is selected from the group consisting of hydrogen, loweralkyl, —(CH₂)_(n)—OH, —(CH₂)_(n)—C(O)OR″ and aryl;

[0045] R⁹ is lower alkyl;

[0046] R¹⁰ is selected from the group consisting of hydrogen, loweralkyl and halogen;

[0047] R¹¹ is hydrogen or alkyl;

[0048] R¹² is —(CH₂)_(n)—N(R)—C(O)-lower alkyl

[0049] R¹³ is hydrogen or lower alkyl;

[0050] R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are independently selected from the groupconsisting of hydrogen, lower alkyl, —(CH₂)_(n)-halogen and loweralkoxy;

[0051] R¹⁸, R¹⁹ and R²⁰ are independently selected from the groupconsisting of hydrogen, lower alkyl, —(CH₂)_(n)-halogen or lower alkoxy;

[0052] R²¹ signifies hydrogen or lower alkyl

[0053] R²² signifies hydrogen, lower alkyl or lower alkyl carrying atleast one substituents selected from hydroxy and halogen;

[0054] R²³ is selected from the group consisting of hydrogen, loweralkyl, lower alkanoyl and nitro;

[0055] R²⁴, R²⁵ and R²⁶ are independently selected from the groupconsisting of hydrogen and lower alkyl;

[0056] n is 0, 1, 2, 3, 4, 5 or 6;

[0057] X is —CH₂—, —O— or —S—; and

[0058] Y is —CH= or —N=;

[0059] and a pharmaceutically acceptable salt thereof; with theexception of 1-methyl-2-phenylethynyl-1H-imidazole,1-methyl-2-(4-methoxy-phenylethynyl)-1H-imidazole,1-methyl-5-phenylethynyl-1H-imidazole, and1-methyl-4-phenylethynyl-1H-imidazole.

[0060] Furthermore, the present invention is a compound of the formula

[0061] wherein

[0062] R¹, R², R³, R⁴ and R⁵ are independently selected from the groupconsisting of hydrogen, lower alkyl, —(CH₂)_(n)-halogen, lower alkoxy,—(CH₂)_(n)—NRR′, —(CH₂)_(n)—N(R)—C(O)-lower alkyl, aryl, unsubstituedheteroaryl and heteroaryl substituted by at least one loweralkylresidues;

[0063] R, R′ and R″ are hydrogen or lower alkyl;

[0064] R⁶ is selected from the group consisting of hydrogen, loweralkyl, —(CH₂)_(n)—C(O)OR and halogen;

[0065] R⁷ is selected from the group consisting of hydrogen,,loweralkyl, —(CH₂)_(n)—C(O)OR′, halogen, nitro, unsubstituted heteroaryl andheteroaryl substituted by lower alkyl or cycloalkyl; and

[0066] R⁸ signifies hydrogen, lower alkyl, —(CH₂)_(n)—OH,—(CH₂)_(n)—C(O)OR″ or aryl;

[0067] or a pharmaceutically acceptable salt thereof.

[0068] The present invention also is a compound of formula

[0069] wherein

[0070] R¹, R², R³, R⁴ and R⁵ are independently selected from the groupconsisting of hydrogen, lower alkyl, —(CH₂)_(n)-halogen, lower alkoxy,—(CH₂)_(n)—NRR′, —(CH₂)_(n)—N(R)—C(O)-lower alkyl, aryl, unsubstitutedheteroaryl and heteroaryl substituted by at least one lower alkyl;

[0071] R and R′ are independently selected from the group consisting ofhydrogen and lower alkyl;

[0072] R⁹ is lower alkyl;

[0073] R¹⁰ is halogen; and

[0074] R¹¹ is selected from the group hydrogen or alkyl;

[0075] or a pharmaceutically acceptable salt thereof

DETAILED DESCRIPTION OF THE INVENTION

[0076] The following definitions of general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination. The term “lower alkyl” used in the presentdescription denotes straight-chain or branched saturated hydrocarbonresidues with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms,such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and thelike.

[0077] The term “cycloalkyl” denotes a saturated carbocyclic groupcontaining from 3 to 7 carbon atoms, preferred are cyclopropyl,cyclopentyl or cyclohexyl.

[0078] The term “halogen” denotes fluorine, chlorine, bromine andiodine.

[0079] The term “lower alkoxy” denotes a lower alkyl group as definedhereinbefore, which is bound via an oxygen atom, e.g. methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy and the like.

[0080] Preferred lower alkanoyl groups are formyl, ethanoyl orpropanoyl.

[0081] Preferred aryl groups are phenyl or naphthyl.

[0082] Heteroaryl groups are selected from furyl, pyrrolyl, thienyl,1H-imidazolyl, 2H-imidazolyl, 4H-imidazolyl, 1H-pyrazolyl, 3H-pyrazolyl,4H-pyrazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1H-[1,2,4]triazolyl,4H-[1,2,4]triazolyl, 1H-[1,2,3]triazolyl, 2H-[1,2,3]triazolyl,4H-[1,2,3]triazolyl, [1,2,4]oxadiazolyl, [1,3,4]oxadiazolyl,[1,2,3]oxadiazolyl, 1H-tetrazolyl, 2H-tetrazolyl, [1,2,3,4]oxatriazolyl,[1,2,3,5]oxatriazolyl, 1,3-thiazolyl, 1,2-thiazolyl, 1H-pentazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, quinolinyl andtheir dihydro derivatives. When the heteroaryl group is substituted, itis preferably subsituted by lower alkyl or cycloalkyl. Preferredheteroaryl groups are pyrrolyl and [1,2,4]oxadiazolyl, eithersubstituted or unsubstituted.

[0083] The term “pharmaceutically acceptable salt” refers to any saltderived from an inorganic or organic acid or base which possesses thedesired pharmacological activity of the parent compound.

[0084] Especially preferred are compounds of formula I for the abovementioned method of treatment, in which A signifies —C≡C− and Bsignifies B1.

[0085] The following are examples of such compounds:

[0086] 3,5-dimethyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethylester,

[0087] 5-methyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethylester,

[0088]2-(3-methoxy-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acidethyl ester,

[0089] 1-methyl-2-phenylethynyl-1H-imidazole,

[0090] 2-(5-nitro-2-phenylethynyl-imidazol-1-yl)-ethanol,

[0091] 2-phenylethynyl-1H-imidazole,

[0092]2-(2,6-dichloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester,

[0093] 5-methyl-1-phenyl-2-phenylethynyl-1H-imidazole-4-carboxylic acidethyl ester,

[0094] 3,5-dimethyl-2-m-tolylethynyl-3H-imidazole-4-carboxylic acidethyl ester,

[0095]2-(3-acetylamino-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester,

[0096]2-[3-(2,5-dimethyl-pyrrol-1-yl)-phenylethynyl]-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester,

[0097]5-(3,5-dimethyl-2-phenylethynyl-3H-imidazol-4-yl)-3-methyl-[1,2,4]oxadiazole,

[0098]3-cyclopropyl-5-(3,5-dimethyl-2-phenylethynyl-3H-imidazol-4-yl)-[1,2,4]oxadiazole,

[0099] 2-(4-chloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester,

[0100] 2-(4-fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester,

[0101] 2-biphenyl-4-ylethynyl-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester,

[0102] 2-(2-fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester,

[0103] 2-(2-fluoro-7phenylethynyl)-1-methyl-1H-imidazole,

[0104] 2-(4-amino-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester,

[0105] 2-(2-chloro-phenylethynyl)-1-methyl-1H-imidazole and

[0106] (4,5-dichloro-2-phenylethynyl-imidazol-1-yl)-acetic acid ethylester.

[0107] Further preferred are compounds of formula I for the abovementioned method of treatment, in which A signifies —C≡C— and Bsignifies B2.

[0108] An example for such a compound is1-methyl-5-phenylethynyl-1H-imidazole.

[0109] Also preferred for the above mentioned method of treatment arecompounds of formula I, in which A signifies —C≡C— and B signifies B3.

[0110] An example for such a compound isN-[2-(5-methoxy-2-phenylethynyl-1H-indol-3-yl)-ethyl]-acetamide.

[0111] Preferred compounds of formula I for the above mentioned methodof treatment are also those, in which A signifies —C≡C— and B signifiesB4.

[0112] The following are examples of such compounds:

[0113] 3-phenylethynyl-4H-5-thia-2,6,9b-triaza-cyclopenta[a]naphthaleneor

[0114] 3-phenylethynyl-4H-5-oxa-2,9b-diaza-cyclopenta[a]naphthalene.

[0115] Further preferred are compounds of formula I for the abovementioned method of treatment, in which A signifies —C≡C— and Bsignifies B5.

[0116] Examples of such compounds are:

[0117]1-chloro-3-(2-methyl-5-nitro-4-phenylethynyl-imidazol-1-yl)-propan-2-ol,

[0118] 3-methyl-5-phenylethynyl-3H-imidazole-4-carbaldehyde,

[0119] 4-phenylethynyl-1H-imidazole,

[0120] 1-methyl-4-phenylethynyl-1H-imidazole and

[0121] 1,2-dimethyl-5-nitro-4-phenylethynyl-1H-imidazole.

[0122] Also preferred are compounds of formula I for the above mentionedmethod of treatment in which A signifies —C≡C— and B signifies B6.

[0123] An example for such a compound is1,3-dimethyl-5-phenylethynyl-1H-pyrazole.

[0124] Further preferred are compounds of formula I for the abovementioned method of treatment, in which A signifies —C≡C—.

[0125] Especially preferred are those compounds of formula I for theabove mentioned method of treatment, in which A signifies —C≡C— and Bsignifies B1.

[0126] The following are examples of such compounds:

[0127] 4,5-diisopropyl-1-methyl-2-styryl-1H-imidazole,

[0128]2-[2-(4-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,

[0129]2-[2-(4-chloro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,

[0130]2-[2-(4-butoxy-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,

[0131]4,5-diisopropyl-2-[2-(4-methoxy-2,3,6-trimethyl-phenyl)-vinyl]-1-methyl-1H-imidazole,

[0132]4,5-diisopropyl-2-[2-(4-methoxy-phenyl)-vinyl]-1-methyl-1H-imidazole,

[0133]2-[2-(4-chloro-3-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,

[0134]2-[2-(4-ethoxy-phenyl)-vinyl4,5-diisopropyl-1-methyl-1H-imidazole,

[0135]4,5-diisopropyl-1-methyl-2-[2-(2,3,4-trimethoxy-phenyl)vinyl]-1H-imidazole,

[0136]2-[2-(2,4-dichloro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazoleand

[0137] 4,5-diisopropyl-1-methyl-2-(2-p-tolyl-vinyl)-1H-imidazole.

[0138] Also preferred are compounds of formula I for the above mentionedmethod of treatment, in which A signifies —C═C— and B signifies B2.

[0139] Examples of such compounds are the following:

[0140] 4-bromo-1-methyl-5-styryl-1H-imidazole and

[0141] 1-methyl-5-styryl-1H-imidazole.

[0142] Further preferred objects of the present invention are compoundsof formula I-A, in which B signifies B1 with the exception of1-methyl-2-phenylethynyl-1H-imidazole and1-methyl-2-(4-methoxy-phenylethynyl)-1H-imidazole.

[0143] The following are examples of such compounds:

[0144] 2-(5-nitro-2-phenylethynyl-imidazol-1-yl)-ethanol,

[0145] 2-phenylethynyl-1H-imidazole,

[0146] 2-(2-fluoro-phenylethynyl)-1-methyl-1H-imidazole,

[0147] 2-(2-chloro-phenylethynyl)-1-methyl-1H-imidazole and

[0148] (4,5-dichloro-2-phenylethynyl-imidazol-1-yl)-acetic acid ethylester.

[0149] More preferred are compounds of formula I-A, in which B signifiesB1 and R⁷ is selected from the group consisting of (CH₂)_(n)—C(O)OR′,unsubstituted heteroaryl and heteroaryl substituted by lower alkyl orcycloalkyl.

[0150] Especially preferred are those, in which R⁷ signifies(CH₂)_(n)—C(O)OR′, wherein n is 0 and R is lower alkyl.

[0151] Examples of such compounds are the following:

[0152] 3,5-dimethyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethylester,

[0153] 5-methyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethylester,

[0154]2-(3-methoxy-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acidethyl ester,

[0155] 2-(2,6-dichlorophenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,

[0156] 5-methyl-1-phenyl-2-phenylethynyl-1H-imidazole-4-carboxylic acidethyl ester,

[0157] 3,5-dimethyl-2-m-tolylethynyl-3H-imidazole-4-carboxylicacid-methyl ester,

[0158]2-(3-acetylamino-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester,

[0159]2-[3-(2,5-dimethyl-pyrrol-1-yl)-phenylethynyl]-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester,

[0160]5-(3,5-dimethyl-2-phenylethynyl-3H-imidazol-4yl)-3-methyl-[1,2,4]oxadiazole,

[0161]3-cyclopropyl-5-(3,5-dimethyl-2-phenylethynyl-3H-imidazol-4-yl)-[1,2,4]oxadiazole,

[0162] 2-(4-chloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester,

[0163] 2-(4-fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester,

[0164] 2-biphenyl-4-ylethynyl-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester,

[0165] 2-(2-fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester, and

[0166] 2-(4-amino-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester.

[0167] Also preferred are compounds of formula I-A, in which B signifiesB4.

[0168] The following are examples of such compounds:

[0169] 3-phenylethynyl-4H-5-thia-2,6,9b-triaza-cyclopenta[a]naphthaleneand

[0170] 3-phenylethynyl-4H-5-oxa-2,9b-diaza-cyclopenta[a]naphthalene.

[0171] Preferred compounds of formula I-A are also those, in which Bsignifies B5 with the exception of1-methyl-4-phenylethynyl-1H-imidazole.

[0172] Examples of such compounds are the following:

[0173]1-chloro-3-(2-methyl-5-nitro-4-phenylethynyl-imidazol-1-yl)-propan-2-ol,

[0174] 3-methyl-5-phenylethynyl-3H-imidazole-4-carbaldehyde,

[0175] 4-phenylethynyl-1H-imidazole and

[0176] 1,2-dimethyl-5-nitro-4-phenylethynyl-1H-imidazole.

[0177] Also preferred is a compound of formula

[0178] wherein R¹, R², R³, R⁴ and R⁵ are independently selected from thegroup consisting of each other, hydrogen, lower alkyl,—(CH₂)_(n)-halogen, lower alkoxy, —(CH₂)_(n)—NRR′,—(CH₂)_(n)—N(R)—C(O)-lower alkyl, aryl, unsubstituted heteroaryl andheteroaryl substituted by at least one lower alkyl; and in which Bsignifies B1 and R⁷ signifies lower alkyl or —(CH₂)_(n)—C(O)OR′.

[0179] Especially preferred are those in which R⁷ is lower alkyl.

[0180] Examples of such compounds are the following:

[0181] 4,5-diisopropyl-1-methyl-2-styryl-1H-imidazole,

[0182]2-[2-(4-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,

[0183] 2-[2-(4-chloro-phenyl)-vinyl]-4,5-diisopropyl1-methyl-1H-imidazole,

[0184]2-[2-(4-butoxy-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,

[0185]4,5-diisopropyl-2-[2-(4-methoxy-2,3,6-trimethyl-phenyl)-vinyl]-1-methyl-1H-imidazole,

[0186]4,5-diisopropyl-2-[2-(4-methoxy-phenyl)-vinyl]-1-methyl-1H-imidazole,

[0187]2-[2-(4-chloro-3-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,

[0188]2-[2-(4-ethoxy-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,

[0189]4,5-diisopropyl-1-methyl-2-[2-(2,3,4-trimethoxy-phenyl)-vinyl]-1H-imidazole,

[0190]2-[2-(2,4-dichloro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazoleand

[0191] 4,5-diisopropyl-1-methyl-2-(2-p-tolyl-vinyl)-1H-imidazole.

[0192] Further preferred compounds of formula I-B are those, in which Bsignifies B2 and R¹⁰ is halogen.

[0193] An example of such a compound is4-bromo-1-methyl-5-styryl-1H-imidazole.

[0194] The present compounds of formula I-A and I-B and theirpharmaceutically acceptable salts can be prepared by methods known inthe art, for example, by processes described below, which processcomprises reacting a compound of the formula

[0195] with a compound of formula

B—X   III

[0196] wherein X signifies halogen or trifluoromethanesulfonyl and

[0197] R¹ to R⁵ have the significances as defined before, to obtain acompound of formula I-A in the case if A signifies —C≡C— and B has thesignificances as defined before;

[0198] or to obtain a compound of formula I-B in the case if A signifies—HC═CH— and B is

[0199] wherein

[0200] R⁶ is selected from the group consisting of hydrogen, loweralkyl, —(CH₂)_(n)—C(O)OR and halogen;

[0201] R⁷ is selected from the group consisting of hydrogen, loweralkyl, —(CH₂)_(n)—C(O)OR′, halogen, nitro, or unsubstituted heteroaryland heteroaryl substituted by lower alkyl or cycloalkyl;

[0202] R⁸ is selected from the group consisting of hydrogen, loweralkyl, —(CH₂)_(n)—OH, —(CH₂)_(n)—C(O)OR″ and aryl;

[0203] R⁹ is lower alkyl;

[0204] R¹⁰ is halogen; and

[0205] R¹¹ is selected from the group hydrogen and alkyl; and ifdesired, converting a compound of formulas I-A or I-B into apharmaceutically acceptable salt.

[0206] This process is catalyzed by palladium(II) salts.

[0207] In accordance with the invention, compounds of formula I, whereinA signifies —C≡C—, are prepared by reacting an acetylene derivative offormula II, for example ethynylbenzene, with a suitable compound offormula III, for example 2-bromo-3,5-dimethyl-3H-imidazole-4-carbokylicacid ester. According to the method as described in Chem. Pharm. Bull.1987, 35(2), 823-828 this palladium catalyzed C-C-coupling reactionrequires the presence of bis(triphenylphosphine)-palladium(II)-chloride,cuprous iodide and triethylamine and is carried out in a polar solventlike dimethylformamide or acetonitrile at a temperature of 90° C. to100° C. within 1.5 to 3 hours. The reaction can also be carried out inthe presence equimolar amounts ofbis(triphenylphosphine)-palladium(II)-chloride and triphenylphosphineand an excess of triethylamine at a temperature of 55° C. within 16hours.

[0208] The phenylethynyl derivatives of formula II are commerciallyavailable or can be easily prepared by methods well known in the art.

[0209] The compounds of formula III are also commercially available orcan be prepared by appropiate methods depending on the heterocyclicsystem B.

[0210] Halogeno-1H-imidazoles of formula III (B=B1) are preparedaccording to methods as described in U.S. Pat. No. (U.S. Pat. No.)4,711,962, U.S. Pat. No. 3,341,548. and Synth. Commun. 1989, 19,2551-2566.

[0211] 2-Trifluoromethanesulfonyl-1H-imidazoles of formula IIIa can beprepared from a 2-oxo-2,3-dihydro-1H-imidazole of formula VI, forexample from5-methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4carboxylic acid ethylester which is obtained according to the method as described in U.S.Pat. No. 3,303,199. The reaction with trifluoromethanesulfonic anhydrideand triethylamine is carried out in dichloromethane at room temperature(Scheme 1, Tf=trifluoromethanesulfonyl).

[0212] 5-(2-Bromo-3,5-dimethyl-3H-imidazol-4-yl)-[1,2,4]oxadiazoles offormula IIIb are obtained by reacting3,5-dimethyl-3H-imidazole-4-carboxylic acid VII withN-hydroxy-carboxamidines of formula VIII in the presence of1,1-carbonyldiimidazole and dimethyl-formamide as solvent to giveimidazolyl-[1,2,4]oxadiazoles of formula IX which are then brominated atroom temperature (Scheme 2, R″ is lower alkyl or cycloalkyl).

[0213] A suitable indole derivative of formula III (B=B3), for exampleN-[2-(2-iodo-5-methoxy-1H-indol-3-yl)-ethyl]-acetamide, can be obtainedin accordance with the method as described in J. Labelled Compd.Radiopharm. 1997, 39, 677-684.

[0214] 3-Iodo-4H-5-thia-2,6,9b-triaza-cyclopenta[a]naphtalenes and3-iodo-4H-5-oxa-2,9b-diaza-cyclopenta[a]naphthalenes of formula III(B=B4) are prepared in analogy to the method as described in EP 0 059390.

[0215] 4-Halogeno-1H-imidazoles of formula III (B=B5) can be obtainedaccording to methods as described for example in J. Med. Chem. 1974,17(9), 1019-1020, Chem. Pharm. Bull. 1994, 42, 1784-1790 or Aust. J.Chem. 1987, 40(8), 1399-1413.

[0216] Compounds of formula III, in which B signifies B6, can beprepared for example in analogy to a method described in Bull. Acad.Sci. USSR Div. Chem. Sci. (Engl. Transl.) 1983, 626-628 and in Izv.Akad. Nauk SSSR Ser. Khim. 1983, 688-690.

[0217] Phenylethenyl derivatives of formula I can be preparedanalogously by reacting a compound of formula III with a phenylethene offormula II.

[0218] Furthermore, compounds of formula I, in which A signifies —C≡C—,and their pharmaceutically acceptable salts can also be obtained byreacting a compound of the formula

[0219] wherein X¹ is halogen,

[0220] with a compound of the formula

[0221] to obtain a compound of formula

[0222] wherein R¹ to R⁵ are as described above and B is

[0223] wherein

[0224] R⁶ is selected from the group consisting of hydrogen, loweralkyl, —(CH₂)_(n)—C(O)OR and halogen;

[0225] R⁷ is selected from the group consisting of hydrogen, loweralkyl, —(CH₂)_(n)—C(O)OR′, halogen, nitro, unsubstituted heteroarylunsubstituted and heteroaryl substituted by lower alkyl or cycloalkyl;

[0226] R⁸ is selected from the group consisting of hydrogen, loweralkyl, —(CH₂)_(n)—OH, —(CH₂)_(n)—C(O)OR″ and aryl;

[0227] R⁹ is lower alkyl;

[0228] R¹⁰ is halogen; and

[0229] R¹¹ is selected from the group consisting of hydrogen or alkyl;and converting a compound of formula I-B into a pharmaceuticallyacceptable salt.

[0230] Thus, compounds of formula I-B are obtained in a Wittig reactionby treating an appropiate aldehyde of formula V, for example4,5-diisopropyl-1-methyl-1H-imidazole-2-carbaldehyde, with a suitablebenzyltriphenylphosphonium halide of formula IV, for examplebenzyltriphenylphosphoniumchloride in the presence of a strong base likea sodium alkoxide, sodium amide or sodium hydride.

[0231] Triphenylphosphonium salts of formula IV are prepared fromtriphenylphosphine (PPh₃) and the appropiate benzyl halides X (Scheme3).

[0232] Aldehydes of formula V can be obtained by methods known in theart. For example, 4,5-diisopropyl-1-methyl-1H-imidazole-2-carbaldehydeis prepared in analogy with a method as described in Inorg. Chim. Acta1999, 296 (1), 208-221, and 5-bromo-3-methyl-3H-imidazole-4-carbaldehydeis obtained in accordance to a method as described in Chem. Pharm. Bull.1994, 42, 1784-1790.

[0233] The pharmaceutically acceptable salts of compounds of formula I-Aand I-B can be manufactured readily according to methods known to thoseskilled in the art taking into consideration the nature of the compoundto be converted into a salt. Inorganic or organic acids such as, forexample, hydrochloric acid, hydrobromic acid, sulphuric acid, nitricacid, phosphoric acid or citric acid, formic acid, fumaric acid, maleicacid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid,p-toluenesulphonic acid and the like are suitable for the formation ofpharmaceutically acceptable salts of basic compounds of formula I.Compounds which contain the alkali metals or alkaline earth metals, forexample sodium, potassium, calcium, magnesium or the like, basic aminesor basic amino acids are suitable for the formation of pharmaceuticallyacceptable salts of acidic compounds.

[0234] The compounds of formula I and their pharmaceutically acceptablesalts are, as already mentioned above, metabotropic glutamate receptorantagonists and can be used for the treatment or prevention of mGluR5receptor mediated disorders, such as acute and/or chronic neurologicaldisorders, cognitive disorders and memory deficits, as well as acute andchronic pain. Treatable neurological disorders are for instanceepilepsy, schizophrenia, anxiety, acute, traumatic or chronicdegenerative processes of the nervous system, such as Alzheimer'sdisease, senile dementia, Huntington's chorea, ALS, multiple sclerosis,dementia caused by AIDS, eye injuries, retinopathy, idiopathicparkinsonism or parkinsonism caused by medicaments as well as conditionswhich lead to glutamate-deficient functions, such as e.g. muscle spasms,convulsions, migraine, urinary incontinence, nicotine addiction,psychoses, opiate addiction, anxiety, vomiting, dyskinesia anddepression. Other treatable indications are restricted brain functioncaused by bypass operations or transplants, poor blood supply to thebrain, spinal cord injuries, head injuries, hypoxia caused by pregnancy,cardiac arrest and hypoglycaemia.

[0235] The compounds of formula I and their pharmaceutically acceptablesalts are especially useful as analgesics. Treatable kinds of paininclude inflammatory pain such as arthritis and rheumatoid disease,vasculitis, neuropathic pain such as trigeminal or herpetic neuralgia,diabetic neuropathy pain, causalgia, hyperalgesia, severe chronic pain,post-operative pain and pain associated with various conditions likecancer, angina, renal or billiay colic, menstruation, migraine and gout.

[0236] The pharmacological activity of all of the example compounds wastested using the following method:

[0237] cDNA encoding rat mGlu 5a receptor was transiently transfectedinto EBNA cells using a procedure described by E. -J. Schlaeger and K.Christensen (Transient gene expression in mammalian cells grown inserum-free suspension culture;

[0238] Cytotechnology, 30: 71-83,1999). [Ca²⁺]i measurements wereperformed on mGlu 5a transfected EBNA cells after incubation of thecells with Fluo 3-AM (obtainable by FLUKA, 0.5 μM final concentration)for 1 hour at 37° C. followed by 4 washes with assay buffer (DMEMsupplemented with Hank's salt and 20 mM HEPES. [Ca²⁺]i measurements weredone using a fluorometric imaging plate reader (FLIPR, Molecular DevicesCorporation, La Jolla, Calif., USA). When compounds were evaluated asantagonists they were tested against 10 μM glutamate as agonist.

[0239] The inhibition (antagonists) curves were fitted with a fourparameter logistic equation giving IC₅₀, and Hill coefficient using theiterative non linear curve fitting software Origin (Microcal SoftwareInc., Northampton, Mass., USA).

[0240] The compounds of the present invention are mGluR 5a receptorantagonists. The compounds show activities, as measured in the assaydescribed above, of 10 μM or less, typically 2 μM or less, andpreferably of 0.02 μM or less.

[0241] The Table I below are shown specific activity data of thecompounds of the present invention derived according to the proceduredescribed above: TABLE I Example No. Compound name IC₅₀ (μM) 13,5-dimethyl-2-phenylethynyl-3H-imidazole-4- 0.25 carboxylic acid ethylester 2 5-methyl-2-phenylethynyl-3H-imidazole-4- 2.40 carboxylic acidethyl ester 3 2-(3-methoxy-phenylethynyl)-3,5-dimethyl-3H- 0.35imidazole-4-carboxylic acid ethyl ester 41-methyl-2-phenylethynyl-1H-imidazole 0.72 52-(5-nitro-2-phenylethynyl-imidazol-1-yl)-ethanol 2.11 62-phenylethynyl-1H-imidazole 0.20 72-(2,6-dichloro-phenylethynyl)-3,5-dimethyl-3H- 10imidazole-4-carboxylic acid ethyl ester 85-methyl-1-phenyl-2-phenylethynyl-1H- <10 imidazole-4-carboxylic acidethyl ester 9 3,5-dimethyl-2-m-tolylethynyl-3H-imidazole-4- 0.13carboxylic acid ethyl ester 102-(3-acetylamino-phenylethynyl)-3,5-dimethyl- 2.123H-imidazole-4-carboxylic acid ethyl ester 11(2-[3-(2,5-dimethyl-pyrrol-1-yl)-phenylethynyl]- 0.183,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester 125-(3,5-dimethyl-2-phenylethynyl-3H-imidazol-4- 0.011yl)-3-methyl-[1,2,4]oxadiazole 142-(4-chloro-phenylethynyl)-3,5-dimethyl-3H- <10 imidazole-4-carboxylicacid ethyl ester 15 2-(4-fluoro-phenylethynyl)-3,5-dimethyl-3H- 0.25imidazole-4-carboxylic acid ethyl ester 162-biphenyl-4-ylethynyl-3,5-dimethyl-3H- 0.21 imidazole-4-carboxylic acidethyl ester 17 2-(2-fluoro-phenylethynyl)-3,5-dimethyl-3H- 0.09imidazole-4-carboxylic acid ethyl ester 182-(2-fluoro-phenylethynyl)-1-methyl-1H- 0.07 imidazole 192-(4-amino-phenylethynyl)-3,5-dimethyl-3H- 1.53 imidazole-4-carboxylicacid ethyl ester 20 2-(2-chloro-phenylethynyl)-1-methyl-1H- 1.10imidazole 21 (4,5-dichloro-2-phenylethynyl-imidazol-1-yl)- 0.52 aceticacid ethyl ester 22 1-methyl-5-phenylethynyl-1H-imidazole 0.22 23N-[2-(5-methoxy-2-phenylethynyl-1H-indol-3-yl)- 0.58 ethyl]-acetamide 243-phenylethynyl-4H-5-thia-2,6,9b-triaza- 0.15 cyclopenta[a]naphthalene25 3-phenylethynyl-4H-5-oxa-2,9b-diaza- 0.07 cyclopenta[a]naphthalene 261-chloro-3-(2-methyl-5-nitro-4-phenylethynyl- 0.23imidazol-1-yl)-propan-2-ol 27 3-methyl-5-phenylethynyl-3H-imidazole-4-1.79 carbaldehyde 28 4-phenylethynyl-1H-imidazole 3.36 291-methyl-4-phenylethynyl-1H-imidazole 0.50 301,2-dimethyl-5-nitro-4-phenylethynyl-1H- 0.02 imidazole 311,3-dimethyl-5-phenylethynyl-1H-pyrazole 5-10 324,5-diisopropyl-1-methyl-2-styryl-1H-imidazole 1.82 332-[2-(4-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1- 5-10methyl-1H-imidazole 34 2-[2-(4-chloro-phenyl)-vinyl]-4,5-diisopropyl-1-5-10 methyl-1H-imidazole 352-[2-(4-butoxy-phenyl)-vinyl]-4,5-diisopropyl-1- 5-10methyl-1H-imidazole 36 4,5-diisopropyl-2-[2-(4-methoxy-2,3,6-trimethyl-5-10 phenyl)-vinyl]-1-methyl-1H-imidazole 374,5-diisopropyl-2-[2-(4-methoxy-phenyl)-vinyl]- 5-101-methyl-1H-imidazole 38 2-[2-(4-chloro-3-fluoro-phenyl)-vinyl]-4,5- 10diisopropyl-1-methyl-1H-imidazole 392-[2-(4-ethoxy-phenyl)-vinyl]-4,5-diisopropyl-1- 10 methyl-1H-imidazole40 4,5-diisopropyl-1-methyl-2-[2-(2,3,4-trimethoxy- 10phenyl)-vinyl]-1H-imidazole 412-[2-(2,4-dichloro-phenyl)-vinyl]-4,5-diisopropyl- 101-methyl-1H-imidazole 424,5-diisopropyl-1-methyl-2-(2-p-tolyl-vinyl)-1H- 3.25 imidazole 434-bromo-1-methyl-5-styryl-1H-imidazole 3.06 441-methyl-5-styryl-1H-imidazole 8.0

[0242] The compounds of formula I and pharmaceutically acceptable saltsthereof can be used as pharmaceutical compositions, e.g. in the form ofpharmaceutical preparations. The pharmaceutical preparations can beadministered orally, e.g. in the form of tablets, coated tablets,dragees, hard and soft gelatine capsules, solutions, emulsions orsuspensions. However, the administration can also be effected rectally,e.g. in the form of suppositories, or parenterally, e.g. in the form ofinjection solutions.

[0243] The compounds of formula I and pharmaceutically acceptable saltsthereof can be processed with pharmaceutically inert, inorganic ororganic carriers for the production of pharmaceutical compositions.Lactose, corn starch or derivatives thereof, talc, stearic acid or itssalts and the like can be used, for example, as such carriers fortablets, coated tablets, dragees and hard gelatine capsules. Suitablecarriers for soft gelatine capsules are, for example, vegetable oils,waxes, fats, semi-solid and liquid polyols and the like; depending onthe nature of the active substance no carriers are, however, usuallyrequired in the case of soft gelatine capsules. Suitable carriers forthe production of solutions and syrups are, for example, water, polyols,sucrose, invert sugar, glucose and the like. Adjuvants, such asalcohols, polyols, glycerol, vegetable oils and the like, can be usedfor aqueous injection solutions of water-soluble salts of compounds offormula I, but as a rule are not necessary. Suitable carriers forsuppositories are, for example, natural or hardened oils, waxes, fats,semi-liquid or liquid polyols and the like.

[0244] In addition, the pharmaceutical compositions can containpreservatives, solubilizers, stabilizers, wetting agents, emulsifiers,sweeteners, colorants, flavorants, salts for varying the osmoticpressure, buffers, masking agents or antioxidants. They can also containstill other therapeutically valuable substances.

[0245] As mentioned earlier, pharmaceutical compositions containing atherapeutically effective amount of compound of formula IA or IB orpharmaceutically acceptable salts thereof and a therapeutically inertexcipient are also an object of the present invention, as is a processfor the production of such pharmaceutical compositions which comprisesbringing one or more compounds of formula IA or IB or pharmaceuticallyacceptable salts thereof and, if desired, one or more othertherapeutically valuable substances into a galenical dosage formtogether with one or more therapeutically inert carriers.

[0246] The dosage can vary within wide limits and will, of course, beadapted to the individual requirements in each particular case. Ingeneral, the effective dosage for oral or parenteral administration isbetween 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day beingpreferred for all of the indications described. The daily dosage for anadult human being weighing 70 kg accordingly lies between 0.7-1400 mgper day, preferably between 7 and 700 mg per day.

[0247] Finally, as mentioned earlier, the use of compounds of formula Iand of pharmaceutically acceptable salts thereof for the production ofpharmaceutical compositions, especially for the for the treatment orprevention of mGluR5 receptor mediated disorders of the aforementionedkind, is also an object of the invention.

[0248] The following examples are provided for illustration of theinvention. They should not be considered as limiting the scope of theinvention, but merely as being representative thereof.

EXAMPLE 1

[0249] 3,5-Dimethyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethylester

[0250] a) 2-Bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethylester

[0251] The title compound was prepared according to the method asdescribed in U.S. Pat. No. 4,711,962.

[0252] b) 3,5-Dimethyl-2-phenylethynyl-3H-imidazole-4-carboxylic acidethyl ester

[0253] In analogy to the method as described in Chem. Pharm. Bull. 1987,35(2), 823-828, 17.5 mg (0.025 mmol)bis-(triphenylphosphine)-palladium-II-chloride, 2.9 mg (0.015 mmol)cuprous iodide, 60.5 mg (0.6 mmol) triethylamine, 32.4 mg (0.3 mmol)ethynylbenzene and 61.8 mg (0.25 mmol)2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester aredissolved in 1 ml DMF and shaken for 3 h at 90° C. The title compound(19.3 mg, 29%, MS: m/e=269.3, [M+H⁺]) was isolated from the reactionmixture by HPLC chromatography (YMC CombiPrep C18 column 50×20 mm,solvent gradient 10-95% CH₃CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm,flow rate 40 ml/min).

[0254]¹H-NMR (400 MHz, CDCl₃, 25° C.): δ (ppm)=1.39 (3H, t, J=7.22 Hz),2.51 (3H, s), 3.99 (3H, s), 4.35 (2H, q, J=7.22 Hz), 7.34-7.40 (3H, m),7.56-7.59 (2H, m).

[0255]¹³C-NMR (100 MHz, CDCl₃, 25° C.): δ (ppm)=14.26, 15.78, 34.31,60.44, 77.83, 94.86, 119.77, 121.14, 128.46, 129.48, 131.82, 134.55,1.47.76, 160.58.

EXAMPLE 2

[0256] 5-Methyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethylester

[0257] a) 2-Bromo-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester

[0258] The compound was prepared according to the method described inU.S. Pat. No. 4,711,962.

[0259] b) 5-Methyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethylester

[0260] The title compound, MS: m/e=255.2 (M+H⁺) was prepared inaccordance with the general method of example 1b from2-bromo-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester.

EXAMPLE 3

[0261]2-(3-Methoxy-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acidethyl ester

[0262] The title compound, MS: m/e=299.3 (M+H⁺) was prepared inaccordance with the general method of example 1b from2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and1-ethynyl-3-methoxy-benzene.

EXAMPLE 4

[0263] 1-Methyl-2-phenylethynyl-1H-imidazole

[0264] The title compound, MS: m/e=183.0 (M+H⁺) was prepared inaccordance with the general method of example 1b from2-iodo-1-methyl-1H-imidazole.

EXAMPLE 5

[0265] 2-(5-Nitro-2-phenylethynyl-imidazol-1-yl)-ethanol

[0266] a) 2-(2-Iodo-5-nitro-imidazol-1-yl)-ethanol

[0267] 2-(2-Iodo-5-nitro-imidazol-1-yl)-ethanol was obtained inaccordance with the method as described in U.S. Pat. No. 3,341,548.

[0268] b) 2-(5-Nitro-2-phenylethynyl-imidazol-1-yl)-ethanol

[0269] The title compound, MS: m/e=258.0 (M+H⁺) was prepared inaccordance with the general method of example 1b from2-(2-iodo-5-nitro-imidazol-1-yl)-ethanol.

EXAMPLE 6

[0270] 2-Phenylethynyl-1H-imidazole

[0271] a) 2-Iodoimidazole

[0272] 2-Iodoimidazole was: prepared in accordance with the method asdescribed in Synth. Commun. 1989, 19, 2551-2566.

[0273] b) 2-Phenylethynyl-1H-imidazole

[0274] The title compound, MS: m/e=169.4 (M+H⁺) was prepared inaccordance with the general method of example 1b from 2-iodoimidazole.

EXAMPLE 7

[0275]2-(2,6-Dichloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester

[0276] The title compound, MS: m/e=197.4 (M+H⁺) was prepared inaccordance with the general method of example 1b from1,3-dichloro-2-ethynyl-benzene and2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.

EXAMPLE 8

[0277] 5-Methyl-1-phenyl-2-phenylethynyl-1H-imidazole-4-carboxylic acidethyl ester

[0278] a) 5-Methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylicAcid Ethyl Ester

[0279] The title compound was obtained by the method as described inU.S. Pat. No. 3,303,199.

[0280] b) 5-Methyl-1-phenyl-2-phenylethynyl-1H-imidazole-4-carboxylicacid ethyl ester

[0281] A mixture of 492 mg (2 mmol)5-methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic acid ethylester, 846 mg (3 mmol) trifluoromethanesulfonic anhydride, 303 mg (3mmol) triethylamine and 10 ml dichloromethane was stirred for 1 h atroom temperature. The volatile components were evaporated under reducedpressure and the obtained residue was filtered over silica gel (ethylacetate/hexane=1:4 as cluent). After evaporation of the solvent underreduced pressure, a yellow oil (463 mg) was obtained. 378 mg of thisoil, 122 mg (1.2 mmol) Phenylacetylene, 70 mg (0.1 mmol)bis-(triphenylphosphine)-palladium-II-chloride, 303mg (3 mmol)triethylamine, and 10 mg (0.05 mmol) of cuprous iodide were dissolved in5 ml DMF and stirred for 1.5 h at 100° C. The reaction mixture wascooled to room temperature, diluted with 30 ml ether, washed with waterand brine and dried over MgSO₄. Evaporation of the solvent gave an oilfrom which the title compound (277 mg, 51%) was isolated by columnchromatography (silica gel, Ethyl acetate/Hexane=2:3 as eluant).

[0282]¹H-NMR (400 MHz, CDCl₃, 25° C.): δ (ppm)=1.44 (3H, t, J=7 Hz),2.47 (3H, s), 4.42 (2H, q, J=7 Hz), 7.20-7.42 (5H, m), 7.34-7.38 (2H,m), 7.53-7.60 (3H, m)

[0283]¹³C-NMR (100 MHz, CDCl₃, 25° C.): δ (ppm) 11.53, 14.94, 60.90,79.34, 92.92, 121.91, 127.79, 128.73, 129.47, 129.86, 130.00, 130.15,131.90, 132.08, 135,42, 137.91, 163.75.

EXAMPLE 9

[0284] 3,5-Dimethyl-2-tolylethynyl-3H-imidazole-4-carboxylic acid ethylester

[0285] The title compound, MS: m/e=283.6 (M+H⁺), was prepared inaccordance with the general method of example 1b from1-ethynyl-3-methyl-benzene and2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.

EXAMPLE 10

[0286]2-(3-Acetylamino-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester

[0287] The title compound, MS: m/e=326.8 (M+H⁺), was prepared inaccordance with the general method of example 1b fromN-(3-ethynyl-phenyl)-acetamide and2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.

EXAMPLE 11

[0288](2-[3-(2,5-Dimethyl-pyrrol-1-yl)-phenylethynyl]-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester

[0289] The title compound, MS: m/e=362.8 (M+H⁺), was prepared inaccordance with the general method of example 1b from2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and1-(3-ethynyl-phenyl)-2,5-dimethyl-1H-pyrrole.

EXAMPLE 12

[0290]5-(3,5-Dimethyl-2-phenylethynyl-3H-imidazol-4-yl)-3-methyl-[1,2,4]oxadiazole

[0291] a) 5-(3,5-Dimethyl-3H-imidazol-4-yl)-3-methyl-[1,2,4]oxadiazole

[0292] A solution of 3,5-dimethyl-3H-imidazole-4-carboxylic acid (1.0 g,7.14 mmol) and 1,1′-carbonyldiimidazole (1.74 g, 10.7 mmol) in DMF (35ml) was stirred at RT for 3 h. N-hydroxy-acetamidine (0.68 g, 9.18 mmol)was added, the reaction mixture was stirred at 16 h at 80° C. evaporatedand dissolved in acetic acid (30 ml). The solution was stirred at

[0293] 100° C. for 2 h, evaporated, poured into sat. NaHCO₃ solution (50ml) and extracted-with dichloromethane (7×30 ml). The combined organiclayers were washed with brine (70 ml), dried (MgSO₄) and evaporated togive the title compound (0.78 g, 61%) as a white solid, m.p. 95° C. andMS: m/e=178.2(M⁺).

[0294] b)5-(2-Bromo-3,5-dimethyl-3H-imidazol-4-yl).-3-methyl-[1,2,4]oxadiazole

[0295] To a stirred solution of5-(3,5-dimethyl-3H-imidazol-4-yl)-3-methyl-[1,2,4]oxadiazol (0.7 g, 3.93mmol) in chloroform (7 ml) was added dropwise at RT a solution ofbromine (0.94 g, 0.30 ml, 5.89 mmol) in chloroform (7 ml). The reactionmixture was stirred at RT for 26 h, evaporated, poured into sat. NaHCO₃solution (40 ml) and extracted with dichloromethane (2×30 ml). Thecombined organic layers were washed with brine (40 ml), dried (MgSO₄)and evaporated to give the crude product as yellow oil (0.84 g).Purification by column chromatography on silica gel (ethyl acetate/MeOH98:2) gave the title compound (0.52 g, 51%) as a white solid, m.p. 89°C. and MS: m/e 256, 258 (M⁺).

[0296] c)5-(3,5-Dimethyl-2-phenylethynyl-3H-imidazol-4-yl)-3-methyl-[1,2,4]oxadiazole

[0297] To a stirred solution of5-(2-bromo-3,5-dimethyl-3H-imidazol-4-yl)-3-methyl-[1,2,4]oxadiazole(0.52 g, 2.02 mmol) in THF (10 ml) was added at RTbis(triphenyl-phosphin)palladium(II)chloride (71 mg, 0.1 mmol),phenylacetylene (0.31 g, 3.03 mmol), triphenylphosphine (27 mg, 0.1mmol) and triethylamine (0.61 g, 6.07 mmol). Through the reactionmixture was bubbled argon for 10 min and stirring was continued at 55°C. for 16 h. The reaction mixture was poured into water (50 ml) andextracted with ethyl acetate (2×50 ml). The combined organic layers werewashed with brine (40 ml), dried (MgSO₄) and evaporated to give thecrude product as yellow oil (0.81 g). Purification by columnchromatography on silica gel (ethyl acetate/toluene 5:1),gave the titlecompound (0.31 g, 55%) as a light yellow solid, m.p. 137° C. and MS:m/e=278.1 (M⁺).

EXAMPLE 13

[0298]3-Cyclopropyl-5-(3,5-dimethyl-2-phenylethynyl-3H-imidazol-4-yl)-[1,2,4]oxadiazole

[0299] a)3-Cyclopropyl-5-(3,5-dimethyl-3H-imidazol-4-yl)-[1,2,4]oxadiazole

[0300] The title compound, off-white solid, m.p. 88° C. and MS:m/e=204.3 (M⁺), was prepared from 3,5-dimethyl-3H-imidazole-4-carboxylicacid and N-hydroxy-cyclopropanecarboxamidine in accordance with thegeneral procedure of example 12a.

[0301] b)5-(2-Bromo-3,5-dimethyl-3H-imidazol-4-yl)-3-cyclopropyl-[1,2,4]oxadiazole

[0302] The title compound, white solid, m.p. 81° C. and MS: m/e=282, 284(M⁺), was prepared by bromination of3-cyclopropyl-5-(3,5-dimethyl-3H-imidazol-4-yl)-[1,2,4]oxadiazole inaccordance with the general method of example 12b.

[0303] c)3-Cyclopropyl-5-(3,5-dimethyl-2-phenylethynyl-3H-imidazol-4-yl)-[1,2,4]oxadiazole

[0304] The title compound, white solid, m.p. 120° C. and MS: m/e=305.2(M+H⁺), was prepared from5-(2-bromo-3,5-dimethyl-3H-imidazol-4-yl)-3-cyclopropyl-[1,2,4]oxadiazoleand phenylacetylene in accordance with the general procedure of example12c.

EXAMPLE 14

[0305] 2-(4-Chloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester

[0306] The title compound, MS: m/e=303.0 (M+H⁺) was prepared inaccordance with the general method of example 1b from2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and1-chloro-4-ethynylbenzene.

EXAMPLE 15

[0307] 2-(4-Fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester

[0308] The title compound, MS: m/e=286.8 (M+H⁺) was prepared inaccordance with the general method of example 1b from2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and1-ethynyl-4-fluorobenzene.

EXAMPLE 16

[0309] 2-Biphenyl-4-ylethynyl-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester

[0310] The title compound, MS: m/e=345.4 (M+H⁺) was prepared inaccordance with the general method of example 1b from2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and4-ethynylbiphenyl.

EXAMPLE 17

[0311] 2-(2-Fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester

[0312] The title compound, MS: m/e=287.4 (M+H⁺) was prepared inaccordance with the general method of example 1b from2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and1-ethynyl-2-fluorobenzene.

EXAMPLE 18

[0313] 2-(2-Fluoro-phenylethynyl)-1-methyl-1H-imidazole

[0314] The title compound, MS: m/e=201.2 (M+H⁺) was prepared inaccordance with the general method of example 1b from2-iodo-1-methyl-1H-imidazole and 1-ethynyl-2-fluorobenzene.

EXAMPLE 19

[0315] 2-(4-Amino-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylicacid ethyl ester

[0316] The title compound, MS: m/e=284.4 (M+H⁺) was prepared inaccordance with the general method of example 1b from2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and4-ethynylaniline.

EXAMPLE 20

[0317] 2-(2-Chloro-phenylethynyl)-1-methyl-1H-imidazole

[0318] The title compound, MS: m/e=217.6 (M+H⁺) was obtained inaccordance with the general method of example 1b from2-iodo-1-methyl-1H-imidazole and 1-chloro-2-ethynylbenzene.

EXAMPLE 21

[0319] (4,5-Dichloro-2-phenylethynyl-imidazol-1-yl)-acetic acid ethylester

[0320] The title compound, MS: m/e=323.0 (M+H⁺) was prepared inaccordance with the general method of example 1b from ethyl(2-bromo-4,5-dichloroimidazole-1-yl)acetate and ethynylbenzene.

EXAMPLE 22

[0321] 1-Methyl-5-phenylethynyl-1H-imidazole

[0322] The title compound, MS: m/e=183.4(M+H⁺) was prepared inaccordance with the general method of example 1b from5-iodo-1-methyl-1H-imidazole.

EXAMPLE 23

[0323] N-[2-(5-Methoxy-2-phenylethynyl-1H-indol-3-yl)-ethyl]-acetamide

[0324] a) N-[2-(2-iodo-5-methoxy-1H-indol-3-yl)-ethyl]-acetamide

[0325] The title compound is obtained fromN-[2-(5-methoxy-indol-3-yl)-ethyl]-acetamide according to the method asdescribed in J. Labelled Compd. Radiopharm. 1997, 39, 677-684.

[0326] b)N-[2-(5-Methoxy-2-phenylethynyl-1H-indol-3-yl)-ethyl]-acetamide

[0327] The title compound, MS: m/e=333.3 (M+H⁺) was prepared inaccordance with the general method of example 1b fromN-[2-(2-iodo-5-methoxy-1H-indol-3-yl)ethyl]-acetamide.

EXAMPLE 24

[0328] 3-Phenylethynyl-4H-5-thia-2,6,9b-triaza-cyclopenta[a]naphthalene

[0329] a) 3-Iodo-4H-5-thia-2,6,9b-triaza-cyclopenta[a]naphthalene

[0330] In analogy to the method as described in EP 0 059 390 the titlecompound was obtained.

[0331] b)3-Phenylethynyl-4H-5-thia-2,6,9b-triaza-cyclopenta[a]naphthalene

[0332] The title compound, MS: m/e=290.3 (M+H⁺) was prepared inaccordance with the general method of example 1b from3-iodo-4H-5-thia-2,6,9b-triaza-cyclopenta[a]naphthalene.

EXAMPLE 25

[0333] 3-Phenylethynyl-4H-5-oxa-2,9b-diaza-cyclopenta[a]naphthalene

[0334] a) 3-Iodo-4H-5-oxa-2,9b-diaza-cyclopenta[a]naphthalene

[0335] 3-Iodo-4H-5-oxa-2,9b-diaza-cyclopenta[a]naphthalene was obtainedin analogy to the method as described EP 0 059 390.

[0336] b) 3-Phenylethynyl-4H-5-oxa-2,9b-diaza-cyclopenta[a]naphthalene

[0337] The title compound, MS: m/e=273.2 (M+H⁺), 545.1 (2M+H⁺), wasprepared in accordance with the general method of example 1b from3-iodo-4H-5-oxa-2,9b-diaza-cyclopenta[a]naphthalene.

EXAMPLE 26

[0338]1-Chloro-3-(2-methyl-5-nitro-4-phenylethynyl-imidazol-1-yl)-propan-2-ol

[0339] a) 1-Chloro-3-(4-iodo-2-methyl-5-nitro-imidazol-1-yl)-propan-2-ol

[0340] 1-Chloro-3-(4-iodo-2-methyl-5-nitro-imidazol-1-yl)-propan-2-olwas obtained by the method as described in J. Med. Chem. 1974, 17(9),1019-20.

[0341] b)1-Chloro-3-(2-methyl-5-nitro-4-phenylethynyl-imidazol-1-yl)-propan-2-ol

[0342] The title compound, MS: m/e=319.7, 321.9 (M+H⁺) was prepared inaccordance with the general method of example 1b from1-chloro-3-(4-iodo-2-methyl-5-nitro-imidazol-1-yl)-propan-2-ol.

EXAMPLE 27

[0343] 3-Methyl-5-phenylethynyl-3H-imidazole-4-carbaldehyde

[0344] a) 5-Bromo-3-methyl-3H-imidazole-4-carbaldehyde

[0345] 5-Bromo-3-methyl-3H-imidazole-4-carbaldehyde was obtained inaccordance with the method as described in Chem. Pharm. Bull. 1994, 42,1784-1790.

[0346] b) 3-Methyl-5-phenylethynyl-3H-imidazole-4-carbaldehyde

[0347] The title compound, MS: m/e=210.6 (M+H⁺) was prepared inaccordance with the general method of example 1b from5-bromo-3-methyl-3H-imidazole-4-carbaldehyde.

EXAMPLE 28

[0348] 4-Phenylethynyl-1H-imidazole

[0349] The title compound, MS: m/e=169.2 (M+H⁺) was prepared inaccordance with the general method of example 1b from 4-bromoimidazoleand ethynylbenzene.

EXAMPLE 29

[0350] 1-Methyl-4-phenylethynyl-1H-imidazole

[0351] The title compound, MS: m/e=183.2 (M+H⁺) was prepared inaccordance with the general method of example 1b from4-iodo-1-methyl-1H-imidazole.

EXAMPLE 30

[0352] 1,2-Dimethyl-5-nitro-4-phenylethynyl-1H-imidazole

[0353] a) 1,2-Dimethyl-4-iodo-5-nitroimidazole

[0354] 1,2-Dimethyl-4-iodo-5-nitroimidazole was obtained according tothe method as described in Aust. J. Chem. 1987, 40(8), 1399-413

[0355] b) 1,2-Dimethyl-5-nitro-4-phenylethynyl-1H-imidazole

[0356] The title compound, MS: m/e=242.4 (M+H⁺) was prepared inaccordance with the general method of example 1b from1,2-dimethyl-4-iodo-5-nitroimidazole.

EXAMPLE 31

[0357] 1,3-Dimethyl-5-phenylethynyl-1H-pyrazole

[0358] a) 5-Iodo-1,3-dimethyl-1H-pyrazole

[0359] The title compound-was obtained according to the method asdescribed in Bull.Acad.Sci.USSR Div.Chem.Sci.(Engl.Transl.) 1983;626-628 and in Izv.Akad.Nauk SSSR Ser.Khim. 1983; 688-690.

[0360] b) 1,3-Dimethyl-5-phenylethynyl-1H-pyrazole

[0361] The title compound, MS: m/e=196.8 (M+H⁺) was prepared inaccordance with the general method of example 1b from5-iodo-1,3-dimethyl-1H-pyrazole.

EXAMPLE 32

[0362] 4,5-Diisopropyl-1-methyl-2-styryl-1H-imidazole

[0363] a) 4,5-Diisopropyl-1-methyl-1H-imidazole-2-carbaldehyde

[0364] 4,5-Diisopropyl-1-methyl-1H-imidazole-2-carbaldehyde was obtainedanalogously to the method as described in Inorg. Chim. Acta 1999,296(1), 208-221.

[0365] b) 4,5-Diisopropyl-1-methyl-2-styryl-1H-imidazole

[0366] 194 mg (0.5 mmol) benzyltriphenylphosphoniumchloride and 97 mg(0.5 mmol) 4,5-diisopropyl-1-methyl-1H-imidazole-2-carbaldehyde wereadded to 1.3 ml of a 0.5 M solution of MeONa in MeOH. The mixture wasshaken at 60° C. for 3 days, then cooled to room temperature. Afteraddition of 0.2 ml formic acid, the title compound (59 mg, 44%, MS:m/e=269.4 [M+H⁺]) was isolated from the reaction mixture by HPLCchromatography (YMC CombiPrep C18 column 50×20 mm, solvent gradient10-95% CH₃CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40ml/min).

EXAMPLE 33

[0367]2-[2-(4-Fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole

[0368] The title compound, MS: m/e=286.8 (M+H⁺), was prepared inaccordance with the general method of example 32b from 4-fluorobenzyltriphenylphosphonium chloride.

EXAMPLE 34

[0369]2-[2-(4-Chloro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole

[0370] The title compound, MS: m/e=302.9 (M+H⁺), was prepared inaccordance with the general method of example 32b from 4-chlorobenzyltriphenylphosphonium chloride.

EXAMPLE 35

[0371]2-[2-(4-Butoxy-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole

[0372] The title compound, MS: m/e=340.9 (M+H⁺), was prepared inaccordance with the general method of example 32b from(4-butoxybenzyl)triphenylphosphonium bromide.

EXAMPLE 36

[0373]4,5-Diisopropyl-2-[2-(4-methoxy-2,3,6-trimethyl-phenyl)-vinyl]-1-methyl-1H-imidazole

[0374] a) 2,3,6-Trimethyl-4-methoxybenzyltriphenyl-phosphonium chloride

[0375] 2,3,6-Trimethyl-4-methoxybenzyltriphenyl-phosphonium chloride wasobtained in accordance with the method as described in Liebigs Ann.Chem. 1984, 10, 1740-5.

[0376] b)4,5-Diisopropyl-2-[2-(4-methoxy-2,3,6-trimethyl-phenyl)-vinyl]-1-methyl-1H-imidazole

[0377] The title compound, MS: m/e=340.9 (M+H⁺), was prepared inaccordance with the general method of example 32b from2,3,6-trimethyl-4-methoxybenzyltriphenyl-phosphonium chloride.

EXAMPLE 37

[0378]4,5-Diisopropyl-2-[2-(4-methoxy-phenyl-vinyl]-1-methyl-1H-imidazole

[0379] The title compound, MS: m/e=298.9 (M+H⁺), was prepared inaccordance with the general method of example 32b from(4-methoxybenzyl)triphenylphosphonium bromide.

EXAMPLE 38

[0380]2-[2-(4-Chloro-3-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole

[0381] a) 4-Chloro-3-fluorobenzyl triphenylphosphonium bromide

[0382] 4-Chloro-3-fluorobenzyl triphenylphosphonium bromide was obtainedaccording to the method as described in EP 0 692 485.

[0383] b)2-[2-(4-Chloro-3-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole

[0384] The title compound, MS: m/e=320.8 (M+H⁺), was prepared inaccordance with the general method of example 32b from4-chloro-3-fluorobenzyl triphenylphosphonium bromide.

EXAMPLE 39

[0385]2-[2-(4-Ethoxy-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole

[0386] The title compound, MS: m/e=312.9 (M+H⁺), was prepared inaccordance with the general method of example 32b from(4-ethoxybenzyl)triphenylphosphonium bromide.

EXAMPLE 40

[0387]4,5-Diisopropyl-1-methyl-2-[2-(2,3,4-trimethoxy-phenyl)-vinyl]-1H-imidazole

[0388] a) Triphenyl-(2,3,4-trimethoxy-benzyl)-phosphonium bromide

[0389] Triphenyl-(2,3,4-trimethoxy-benzyl)-phosphonium bromide wasobtained according to the method as described in DE 43 07 049.

[0390] b)4,5-Diisopropyl-1-methyl-2-[2-(2,3,4-trimethoxy-phenyl)-vinyl]-1H-imidazole

[0391] The title compound, MS: m/e=359.0 (M+H⁺), was prepared inaccordance with the general method of example 32b fromtriphenyl-(2,3,4-trimethoxy-benzyl)-phosphonium bromide.

EXAMPLE 41

[0392]2-[2-(2,4-Dichloro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole

[0393] The title compound, MS: m/e=336.8 (M+H⁺), was prepared inaccordance with the general method of example 32b from2,4-ichlorobenzyltriphenylphosphonium chloride.

EXAMPLE 42

[0394] 4,5-Diisopropyl-1-methyl-2-(2-p-tolyl-vinyl)-1H-imidazole

[0395] The title compound, MS: m/e=282.9 (M+H⁺), was prepared inaccordance with the general method of example 32b from4-methylbenzyltriphenylphosphonium bromide.

EXAMPLE 43

[0396] 4-Bromo-1-methyl-5-styryl-1H-imidazole

[0397] a) 5-Bromo-3-methyl-3H-imidazole-4-carbaldehyde

[0398] 5-Bromo-3-methyl-3H-imidazole-4-carbaldehyde was obtained by themethod as described in Chem. Pharm.,Bull. 1994, 42, 1784-1790.

[0399] 4-Bromo-1-methyl-5-styryl-1H-imidazole

[0400] The title compound, MS: m/e=263.6 (M+H⁺), was prepared inaccordance with the general method of example 21b from5-bromo-3-methyl-3H-imidazole-4-carbaldehyde.

EXAMPLE 44

[0401] 1-Methyl-5-styryl-1H-imidazole

[0402] The title compound was obtained according to the method asdescribed in Chem. Pharm. Bull. 1987; 35, 823-828.

EXAMPLE A

[0403] Tablets of the following composition can be produced in aconventional manner: mg/Tablet Active ingredient 100 Powdered. lactose 95 White corn starch  35 Polyvinylpyrrolidone  8 Na carboxymethylstarch 10 Magnesium stearate  2 Tablet weight 250

EXAMPLE B

[0404] Tablets of the following composition can be produced in aconventional manner: mg/Tablet Active ingredient 200 Powdered. lactose100 White corn starch  64 Polyvinylpyrrolidone  12 Nacarboxymethylstarch  20 Magnesium stearate  4 Tablet weight 400

EXAMPLE C

[0405] Capsules of the following composition can be produced: mg/CapsuleActive ingredient  50 Crystalline. lactose  60 Microcrystallinecellulose  34 Talc  5 Magnesium stearate  1 Capsule fill weight 150

[0406] The active ingredient would be prepared having a suitableparticle size, then the crystalline lactose and the microcrystallinecellulose can be homogeneously, mixed with one another, sieved andthereafter talc and magnesium stearate admixed. The final mixture can befilled into hard gelatine capsules of suitable size.

1. A compound of formula

wherein R¹, R², R³, R⁴ and R⁵ are independently selected from the groupconsisting of hydrogen, lower alkyl, —(CH₂)_(n)-halogen, lower alkoxy,—(CH₂)_(n)—NRR′, —(CH₂)_(n)—N(R)—C(O)-lower alkyl, aryl or unsubstitutedheteroaryl , heteroaryl substituted by at least one lower alkyl; R, R′and R″ are independently selected from the group consisting of hydrogenand lower alkyl; R⁶ is selected from the group consisting of hydrogen,lower alkyl, —(CH₂)_(n)—C(O)OR and halogen; R⁷ is selected from thegroup consisting of hydrogen, lower alkyl, —(CH₂)_(n)—C(O)OR′, halogen,nitro, unsubstituted heteroaryl and heteroaryl substituted by loweralkyl or cycloalkyl; and R⁸ is selected from the group consisting ofhydrogen, lower alkyl, —(CH₂)_(n)—OH, —(CH₂)_(n)—C(O)OR″ or aryl; or apharmaceutically acceptable salt thereof:
 2. A compound according toclaim 1, wherein R⁷ signifies lower alkyl or —(CH₂)_(n)—C(O)OR′.
 3. Thecompound according to claim 1, which is4,5-diisopropyl-1-methyl-2-styryl-1H-imidazole.
 4. The compoundaccording to claim 1, which is2-[2-(4-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole. 5.The compound according to claim 1, which is2-[2-(4-chloro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole. 6.The compound according to claim 1, which is2-[2-(4-butoxy-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole. 7.The compound according to claim 1, which is4,5-diisopropyl-2-[2-(4-methoxy-2,3,6-trimethyl-phenyl)-vinyl]-1-methyl-1H-imidazole.8. The compound according to claim 1, which is4,5-diisopropyl-2-[2-(4-methoxy-phenyl)-vinyl]-1-methyl-1H-imidazole. 9.The compound according to claim 1, which is2-[2-(4-chloro-3-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole.10. The compound according to claim 1, which is2-[2-(4-ethoxy-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole. 11.The compound according to claim 1, which is4,5-diisopropyl-1-methyl-2-[2-(2,3,4-trimethoxy-phenyl)-vinyl]-1H-imidazole.12. The compound according to claim 1, which is2-[2-(2,4-dichloro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole.13. The compound according to claim 1, which is4,5-diisopropyl-1-methyl-2-(2-p-tolyl-vinyl)-1H-imidazole.
 14. Apharmaceutical composition comprising a therapeutically effective amountof a compound of formula

wherein R¹, R², R³, R⁴ and R⁵ are independently selected from the groupconsisting of hydrogen, lower alkyl, —(CH₂)_(n)-halogen, lower alkoxy,—(CH₂)_(n)—NRR′, —(CH₂)_(n)—N(R)—C(O)-lower alkyl, aryl or unsubstitutedheteroaryl , heteroaryl substituted by at least one lower alkyl; R, R′and R″ are independently selected from the group consisting of hydrogenand lower alkyl; R⁶ is selected from the group consisting of hydrogen,lower alkyd —(CH₂)_(n)—C(O)OR and halogen;. R⁷ is selected from thegroup consisting of hydrogen, lower alkyl, —(CH₂)_(n)—C(O)OR′, halogen,nitro, unsubstituted heteroaryl and heteroaryl substituted by loweralkyl or cycloalkyl; and R⁸ is selected from the group consisting ofhydrogen, lower alkyl, —(CH₂)_(n)—OH, —(CH₂)_(n)—C(O)OR″ or aryl; or apharmaceutically acceptable salt thereof in a racemic or opticallyactive form and a pharmaceutically inert carrier.
 15. A pharmaceuticalcomposition according to claim 14 wherein the compound is selected fromthe group consisting of 4,5-diisopropyl-1-methyl-2-styryl-1H-imidazole,2-[2-(4-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,2-[2-(4-chloro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,2-[2-(4-butoxy-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,4,5-diisopropyl-2-[2-(4-methoxy-2,3,6-trimethyl-phenyl)-vinyl]-1-methyl-1H-imidazole,4,5-diisopropyl-2-[2-(4-methoxy-phenyl)-vinyl]-1-methyl-1H-imidazole,2-[2-(4-chloro-3-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,2-[2-(4-ethoxy-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,4,5-diisopropyl-1-methyl-2-[2-(2,3,4-trimethoxy-phenyl)-vinyl]-1H-imidazole,2-[2-(2,4-dichloro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazoleand 4,5-diisopropyl-1-methyl-2-(2-p-tolyl-vinyl)-1H-imidazole.
 16. Apharmaceutical composition according to claim 14 wherein the compound is4,5-diisopropyl-1-methyl-2-[2-(2,3,4-trimethoxy-phenyl)-vinyl]-1H-imidazole.